tbuckley/cabot-search huggingface dataset:
Abstract P2023: Non-cardiomyocytes From Chronic Unloaded Post LVAD Heart Form Organized Complex Neovascular Structures When Compared To Those From Heart Failure.
Authors: Rajul Ranka, John P Cooke, Arvind Bhimaraj, Keith A Youker
Journal: Circulation Research (2022)

Introduction: Chronic unloading of the left ventricle (LV) has shown increased endothelial density suggestive of a vascular recovery. Mechanisms of such neovascularization have not been fully explored. Hypothesis: Non-myocyte transitions may play a role in neovascularization in cardiac recovery. Methods: We utilized fresh cardiac tissue obtained from patients at the time of LVAD (pre-LVAD core - representing HF) and from a LVAD patient at the time of transplant (Post-LVAD-representing chronic unloaded heart). Using disaggregation, cardiac non-myocytes were isolated, and the resulting pellet of cardiac non-myocytes was divided and plated in both fibroblast (FGM) and endothelial (EGM) growth media. Results: Cells from post-LVAD patient in EGM (grown on glass coverslip) showed a complex organizational network with the presence of CD31+ cells in vessel like structures surrounded by vimentin positive cells (See Figure). These networks were not observed in any of the other culture conditions. We also observed that cells from post-LVAD grew much faster compared to pre-LVAD cells. Conclusions: To our knowledge, this is the first-time disaggregated cells from human heart samples have been studied in culture. These preliminary observations support the ability of non-cardiomyocytes in a chronic unloaded and rested heart to form neovascular structures not seen in cells from the diseased state of heart failure. This platform can serve to further understand the behavior and role of complex non-myocyte interactions in cardiac recovery.
Abstract P1101: Mitochondrial Ca Uniporter Complex, ROS And CaT Alternans
Authors: Yuriana Oropeza-Almazan, Lothar A Blatter
Journal: Circulation Research (2022)

Background: Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternation in CaT amplitude and is causally linked to atrial fibrillation (AF). Inhibition of mitochondrial Ca uptake via the mitochondrial Ca uniporter complex (MCUC) facilitates CaT alternans and can lead to an increase in mitochondrial reactive oxygen species(ROS) production that compromises the cellular antioxidative capacity. The objective was to determine the mechanisms through which mitochondrial Ca uptake and ROS production determine the susceptibility of atrial cells to develop CaT alternans. Methods: CaT alternans was measured in single rabbit left atrial myocytes with fluorescence microscopy using the fluorescent Ca indicator Cal-520/AM, and for simultaneous measurements of ROS and alternans, cells were loaded with CM-DCFDA and Cal-590/AM. CaT alternans was induced by increasing the pacing frequency until stable CaT alternans was observed. The degree of alternans was quantified as the alternans ratio (AR = 1 – S/L, where S/L is the ratio of the small to the large amplitude of a pair of alternating CaTs). Results: Exposure of LA myocytes to the specific MCUC inhibitor Ru360 increased the AR by 86%. However, the subsequent stimulation of mitochondrial Ca uptake with the MCUC activator spermine (Spm) decreased AR by 79% (p=0.028). Quercetin (a O2 .- scavenger) and Tempol (a superoxide dismutase mimetic) lowered CaT AR by 96% (p=0.0007) and 79% (p=0.0029), respectively. An oxidative challenge with tert-butylhydroperoxide (tBHP) increased AR by 140% (p=&lt;0.0001), and the reducing agent dithiothreitol (DTT) decreased AR by 39% (p=0.0194). Moreover, DTT treatment rescued CaT alternans previously enhanced by tBHP. During CaT alternans the rate of ROS production increased by 23% (p=0.026), however Spm treatment attenuated the increased ROS production. Conclusion: An oxidizing environment facilitates the development of CaT alternans. During CaT alternans mitochondrial ROS formation is increased and involves MCUC activity.
Abstract P2089: Sex Differences In Racism And Renal Injury Biomarker Association In African Americans
Authors: Mildred A Pointer, Thais Holanda, Dwayne Muhammad, Claudia Alberico, Nikia Laurie, Deepak Kumar
Journal: Circulation Research (2022)

Among the general population of African Americans (AAs) the risk for kidney disease is approximately 4-fold greater than Caucasians. However, the risk for kidney disease can be as high as 10-fold greater among hypertensive young African American (AA) males. The reason for this disparity remains elusive, but environmental stress has been identified as a contributor to disease risk among Blacks. Male (n=78) and female (n=91) AAs were administered the perceived racism scale (PRS) to investigate the relationship between perceived racism and biomarkers of stress (cortisol), hypertension (systolic and diastolic blood pressure; SBP/DBP, respectively), obesity (body mass index, BMI), and diabetes (CRP, and C peptide). Resting heart rate (HR) and BMI were measured; a blood sample collected to measure cortisol as well as C reactive protein (CRP) and C peptide (both biomarkers of diabetes); and urine was collected for measuring albumin to creatinine ratio (A:C, index of renal injury). There were no sex differences in age (36 ± 2 vs 33 ± 2), SBP (127± 13 vs 124 ± 2), DBP (72 ± 1 vs 69 ± 1), but A:C was higher in males (28 ± 12 vs 21 ± 4; p&lt;0.003; males vs females, respectively). Males had higher job domain PRS scores (20 ± 2 vs 14 ± 1, p&lt;0.01 male vs female, respectively) and PRS was positively correlated with cortisol (r=0.54, p&lt;0.05) in males only. Furthermore, job PRS was positively correlated with biomarkers of obesity (BMI: r=0.419, p&lt;0.004), hypertension (SBP, DBP: r=0.521, r=0.480; p&lt;0.002, &lt;0.009, respectively), and diabetes (C peptide: r=0.468, p&lt;0.03) in males but not females. Interestingly, job PRS scores (r=0.498, p&lt;0.005) as well as hypertension (SBP/DBP: r=0.398, r=0.611; p&lt;0.03, p&lt;0.001, respectively) and diabetes (CRP: r=0.812, p&lt;0.001) biomarkers were positively correlated with A:C in males but not females. These findings support the idea that the increased risk for kidney injury in young hypertensive AA males results from environmental stress of racism that activates biological pathways leading to cardiovascular and kidney disease. More studies are needed to identify the underlying pathways between perceived racism and promotion of cardiometabolic disease.
Abstract P3064: Immunoengineered Tantalum Carbide Mxene Quantum Dots For Prevention Of Transplant Vasculopathy
Authors: Sanjiv Dhingra, Weiang Yan, ALIREZA RAFIEERAD, Keshav Narayan Alagarsamy, Rakesh C Arora
Journal: Circulation Research (2022)

Transplant vasculopathy is an aggressive form of atherosclerosis that manifests uniquely in transplanted hearts, lungs, and kidneys. Recently, immunoengineered transition metal carbides, or MXenes, have demonstrated unique immunomodulatory properties and this can potentially be leveraged to prevent transplant vasculopathy. Here, we present the synthesis, characterization and application of novel zero-dimensional tantalum carbide (Ta 4 C 3 T x ) MXene quantum dots (MQDs) for immunomodulation. A facile hydrofluoric acid-free etching protocol was developed to synthesize zero-dimensional Ta 4 C 3 T x MQDs from Ta 4 AlC 3 MAX phase. The resultant MQDs are 3 to 7 nm in diameter and are surface modified with carboxyl, hydroxyl, and amine functional groups for biological interactions. Immunomodulation was assessed in vitro through co-cultures of human umbilical vein endothelial cells (ECs) and peripheral blood mononuclear cells. We found that MQDs interact with activated human ECs in vitro to reduce activation and pro-inflammatory Th1 polarization of allogeneic CD4 + lymphocytes. Mechanistically, we showed using quantitative PCR that treatment with MQDs significantly increased endothelial surface expression of the T-cell co-inhibitory molecule PD-L1 and decreased the co-stimulatory molecule CD86. Furthermore, exploratory bulk RNA-sequencing of co-cultured lymphocytes showed decreases in the immunologic signatures of naïve T-cells and increases in the immunologic signatures of CD25 + regulatory T-cells, suggesting activation of this suppressive T-cell population. Finally, when applied in an in vivo rat model of transplant vasculopathy, treatment with MQDs reduced lymphocyte infiltration and preserved medial smooth muscle cell integrity within transplanted aortic segments. These findings suggest that these novel MQDs have potential as an effective treatment to ameliorate transplant vasculopathy.
Changes in Cerebral Perfusion According to Single Photon Emission Computed Tomography after Coronary Artery Bypass Grafting and Simultaneous Interventions on the Carotid and Coronary Arteries
Authors: A. A. Korotkevich, S. E. Semenov, O. V. Maleva, O. A. Trubnikova
Journal: Radiology - Practice (2022)

Goal of investigation was comparison and assessment of the state of cerebral perfusion according to SPECT data after coronary artery bypass grafting and simultaneous surgical intervention on the carotid and coronary arteries. Brain perfusion data were studied in 34 cardiac surgical patients who underwent surgical correction under conditions of cardiopulmonary bypass: simultaneous intervention on the coronary and carotid arteries (n = 21) and coronary artery bypass grafting (n = 13). The study of the brain was carried out by SPECT with the radiopharmaceutical 99mTc-HMPAO (Ceretek). In the group with CABG, there was a statistically significant decrease in the CBF values in the region of the caudate nucleus on the right, in both occipital and parietal lobes (p = 0.004193). In the group with simultaneous interventions, a significant decrease in the CBF indices in the right occipital and left parietal lobes (p = 0.020672), an increase in the indices in the left temporal lobe (p = 0.011286) was revealed. CBF indicators in the group with simultaneous interventions are significantly lower than those in the group with CABG both in the preoperative and postoperative periods. The data obtained indicate that patients with combined atherosclerotic lesions of the coronary and carotid arteries have significantly lower values of the CBF in comparison with patients with isolated changes in the coronary arteries. Coronary artery bypass grafting and simultaneous surgical interventions on the carotid and coronary arteries under cardiopulmonary bypass may be accompanied by a significant decrease in regional cerebral blood flow in certain areas of the brain, and these changes in the CABG group can be traced in a larger number of analyzed areas.
Abstract P2091: Age-dependent Remodeling Of The Perinexus Modulates The Phenotype And Arrhythmic Risk Of Long Qt Syndrome Type 3
Authors: Xiaobo Wu, David King, Gregory Hoeker, Scott R Johnstone, Robert G Gourdie, Seth Weinberg, Steven Poelzing
Journal: Circulation Research (2022)

Background: The Long-QT Syndrome Type 3 (LQT3) is characterized by action potential duration (APD) prolongation due to cardiac voltage-gated sodium channel (Nav1.5) gain of function. Arrhythmia risk increases with age in LQT3 patients, but it is unknown whether this is due to progressive APD prolongation. Recent studies have shown that the LQT3 phenotype can be exacerbated by widening the perinexus, an intercalated disc nanodomain adjacent to gap junctions. However, it remains unclear if the perinexus mediates the LQT3 phenotype during aging. Objective: To investigate the role of the perinexus during aging in LQT3. Methods: Ventricular epicardial APD was obtained by optically mapping Langendorff-perfused adult (3-month) and aged (15-month) guinea pig hearts. LQT3 phenotype was induced with anemone toxin (ATXII), and the perinexus was widened with an intercalated disc adhesion inhibitor (βadp1). Perinexal width (Wp) was quantified by transmission electron microscopy. Susceptibility to arrhythmia was assessed with burst pacing in the absence and presence of βadp1 and evaluated from electrocardiograms (ECG). Results: APD was not different between adult and aged hearts at baseline, with ATXII, or ATXII+βadp1. Wp was significantly wider in adult LQT3 hearts either without or with βadp1 relative to aged hearts (without βadp1: 29.6±2.5 vs 22.9±3.8 nm; with βadp1: 38.3±1.7 vs 29.9±1.2 nm). These data suggest the perinexus narrows with aging and attenuates previously reported cellular APD prolongation such that there is no difference in whole-heart, epicardial APD between adult and aged LQT3 hearts. However, ECG Tpeak-Tend interval was not prolonged in adult, but significantly prolonged in aged hearts after treatment with ATXII+βadp1 (18.7±5.6 vs 35.5±11.5 ms), suggesting that βadp1 increases transmural dispersion of repolarization during aging in LQT3. Furthermore, ATXII+βadp1 did not induce arrhythmias in adult (0/6) but was arrhythmogenic in aged hearts (3/5). Conclusions: Perinexal narrowing associated with aging attenuates APD prolongation and reduces arrhythmic risk in aged LQT3 hearts. Loss of perinexal adhesion in aged LQT3 hearts results in significant and heterogeneous APD prolongation and increased risk of arrhythmia.
Respiratory muscle fatigue limiting physical exercise?
Authors: JW Fitting
Journal: European Respiratory Journal (1991)

Inspiratory muscle fatigue has been documented during loaded breathing or acute respiratory failure, but its role in exercise limitation is still undetermined. Electromyographic (EMG) signs of diaphragmatic fatigue develop in normal subjects hyperventilating above 70% of maximal voluntary ventilation (MVV), a ventilatory level commonly attained at peak exercise. EMG signs of diaphragmatic fatigue also occur during high power cycling exercise in normal subjects and chronic obstructive pulmonary disease (COPD) patients. However, a loss of respiratory muscle strength has rarely been documented following strenuous physical exercise with techniques independent of the subjects' collaboration. Prior inspiratory muscle fatigue decreases exercise tolerance in normal subjects but its effect is largely unknown in COPD patients. Respiratory muscle rest by negative pressure ventilation was reported to improve exercise tolerance in COPD, but this beneficial effect was not confirmed by controlled studies. The effect of inspiratory muscle training on exercise tolerance is still undefined by existing data, in part because of differences in methods and selection criteria between studies. Although respiratory muscle fatigue may occur during exercise, it is not clearly established whether interventions directed at respiratory muscles may improve exercise tolerance in COPD.
Abstract P2076: β-hydroxybutyrate Administered At Reperfusion Alleviates Myocardial Ischemia-reperfusion Injury By Enhancing Autophagy And Mitochondrial Homeostasis
Authors: Yuxin Chu, Lihao He, Yutao Hua, Jin He, Yunxi Chen, Gloria Benavides, Victor Darley-Usmar, Martin E Young, Cheng Zhang, Min Xie
Journal: Circulation Research (2022)

Introduction: ST-elevation myocardial infarction (STEMI) is the leading cause of heart failure. Ischemia/reperfusion (I/R) injury after revascularization contributes ~50% of infarct size, which we don’t have a clinical therapy. β-hydroxybutyrate (β-OHB) is a metabolite that increases during stress. In addition to providing energy, it serves as a signaling molecule (such as histone deacetylase inhibitor) to regulate many protective processes. Increasing the β-OHB level before I/R is cardiac protective. However, it has not been tested when administered at reperfusion. Hypothesis: The physiological concentration of β-OHB administered at the time of reperfusion reduces I/R injury by enhancing autophagy and mitochondrial homeostasis. Methods: C57BL6 wild-type mice were randomized into 2 groups and subjected to I/R surgery (I: 45 mins; R: 24 hrs). At reperfusion, normal saline or 10 mmol/kg of β-OHB (4-6 mM blood level) was given intraperitoneally. Echo was used to evaluate cardiac functions. We measured Infarct size, autophagic flux, and mitochondrial DNA levels in the heart. CAG-RFP-GFP-LC3 (RFLC3) mice were used to detect autophagic flux. Neonatal rat ventricular myocytes (NRVMs) were subjected to simulated I/R to test the effect of β-OHB in vitro . Small interfering RNA of ATG7 gene was used to assess the role of autophagy. Seahorse assay was performed to evaluate mitochondrial function after I/R. Results: β-OHB gave at reperfusion reduced infarct size by 50% (N=15 in control and N=11 in β-OHB group), and preserved systolic function in mice. In the border zone, the LC3II and the mtDNA level increased, and β-OHB increased autophagic flux in RFLC3 mice (N=5). In NRVMs subjected to I/R, β-OHB increased histone acetylation, cell viability, and maintained mitochondrial homeostasis (mitochondrial mass, membrane potential), and reduced ROS generation (N=4-6). Seahorse assay showed β-OHB enhanced ATP production after I/R. ATG7 knockdown blocked the protective effect of β-OHB in NRVMs. Conclusions: β-OHB administered at reperfusion reduces infarct size by increasing autophagic flux and maintaining mitochondrial homeostasis. Since β-OHB has been used in heart failure patients safely, it is a viable therapeutics to reduce infarct size in STEMI patients.
Abstract P2014: Chitinase-3-like-1 Is A Neutrophil Secreted Factor That Antagonizes Replacement Fibrosis And Exacerbates Cardiac Dysfunction After Myocardial Infarction.
Authors: Jonah Stephan, Zhen Gu, Zoubul Taylor, Sujith Dassanayaka, Robert Brainard, Steven P Jones, Marcin Wysoczynski
Journal: Circulation Research (2022)

Patient studies show that chitinase 3-like 1 (CHI3L1) is a novel biomarker of coronary artery disease (CAD). Furthermore, CHI3L1 plasma level is a strong predictor of all-cause of mortality in patients with CAD, and is a strong indicator of heart failure progression. Studies from our lab revealed that CHI3L1 is elevated in hearts after MI, and systemic administration of CHI3L1 in mice exacerbated post-MI fibrosis and left ventricular dysfunction. The goal of the current study was to delineate the mechanism of CHI3L1 secretion after MI and test the impact of CHI3L1 on post-MI replacement fibrosis. We found that CHI3L1 levels were rapidly increased in infarcted regions of LV at 2 d after MI and remained significantly elevated at 7 and 35 d (n=5-11/group, p&lt;0.05). More detailed analysis revealed that neutrophils are the main source of CHI3L1. Protein CHI3L1 expression in neutrophils was 3-4 orders of magnitude higher compared with cardiac fibroblasts, macrophages, endothelial cells, and cardiomyocytes (n=3-5, p&lt;0.0001). Next, we found that Chil1 -/- subjected to permanent coronary artery ligation showed decreased end-systolic and diastolic volumes and increased ejection fraction measured at 7 and 35 d with echocardiography (n=7-10/group, p&lt;0.05 at 7 d; n=16-20/group, p&lt;0.05 at 35 d). Histological analysis of hearts displayed no change in scar size but left ventricular expansion index was reduced and the infarcted wall thickness was increased in Chil1 -/- mice compared to their Chil1 +/+ controls (n=16-18/group, p&lt;0.01). We found no difference in cardiomyocyte cross-sectional area (WGA staining) and capillary density (isolectin B4 staining). These data provide proof of principle evidence that CHI3L1 is a neutrophil secreted factor that has an adverse effect on replacement fibrosis after MI. Future efforts will focus on the mechanism of actions of CHI3L1 and the identification of strategies to inhibit detrimental actions of CHI3L1 on replacement fibrosis and heart failure.
Abstract P3004: Small Leucine-Rich Proteoglycan Asporin Represses Smooth Muscle Cell Proliferation And Regulates Pulmonary Hypertension Development
Authors: Lejla Medzikovic, Gregoire Ruffenach, JASON HONG, Laila Aryan, Mansoureh Eghbali
Journal: Circulation Research (2022)

Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular lung disease characterized by increased pressure in the pulmonary arteries leading to cardiac right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current PAH therapies merely improve symptoms temporarily and patients often need lung and heart transplantation. As such, there is dire need for new insights into PAH pathophysiology to find novel therapeutic approaches. A key mechanism driving PAH is medial hyperplasia resulting from enhanced pulmonary arterial smooth muscle cell (PASMC) proliferation. Using an unbiased bioinformatics approach in an online-available microarray expression dataset of dissected pulmonary arteries (PA) from PAH patients, we discovered a novel gene, small leucine-rich proteoglycan Asporin (Aspn), which is highly and significantly upregulated in PAH compared to otherwise-healthy donor PA. Further bioinformatic analysis at a single-cell level in an online human lung dataset revealed that Aspn is most highly expressed in pulmonary SMC. We validated higher Aspn mRNA expression in human lungs and PASMC from PAH patients compared to controls, supporting our bioinformatics approach. Moreover, Aspn protein expression is elevated in PASMC in lung tissue sections from PAH patients compared to donors . Functionally, silencing Aspn in PASMC from PAH patients promoted proliferation. To find potential downstream mediators of Aspn, STRING database analysis revealed that Aspn binds to the pro-proliferative mediator TGFβ1. Accordingly, TGFβ1 downstream mediator p-SMAD2 is enhanced upon Aspn silencing in PASMC. In vivo , intratracheal delivery of Aspn siRNA in rats aggravated Sugen/Hypoxia-induced PH, as assessed by RV systolic pressure, echocardiography, and pulmonary vascular remodeling. Taken together, we hypothesize that elevated Aspn expression in PAH is a compensatory mechanism that inhibits PASMC proliferation, leading to decreased PA vascular remodeling, and that Aspn may be a novel therapeutic target against PAH.
Dyspnoea: assessment and pharmacological manipulation
Authors: RD Stark
Journal: European Respiratory Journal (1988)

A recent meeting of the European Society for Clinical Respiratory Physiology, held in Antwerp, focused on the mechanisms and management of respiratory symptoms.Dyspnoea received particular attention and this review is based on a talk presented at that meeting.The clinical problem posed by dyspnoea, or breathlessness, is of considerable magnitude.Precise data on its prevalence a re lacking but it is the most common symptom in patients with cardiorespiratory disease.Many chronic diseases are associated with dyspnoea, notably cardiac failure and chronic obstructive pulmonary disease.Extrapolation from the epidemiological survey of the Respiratory Diseas~ Study Group of the RCGP [I) would suggest that.m the UK alone, approximately 750,000 patients with chronic bronchitis experience dyspnoea induced by walking on level ground.A therapeutic agent which reduces the sensation of dyspnoea would be expected to improve the quality of life for the patient by delaying the restrictions on Hfestyle imposed by breathlessness and by mitigating a symptom which causes distress and induces anxiety.This would be no substitute for specific therapy directed at the underlying disease process, but could be of value when the patholot:,ry is not reversible.Close analogies exist with the use of analgesics to treat pain.Discovery of drugs to reduce dyspnoea is difficult because the pathophysiological mechanisms are still in dispute.In addition, animal models are limited in the study of sensations.In this laboratory known pharmacological agents were used in studies on man to discover the possible mechanisms of dyspnoea.No progress could be made until methods were available for assessing breathlessness.Precision was necessary in these assessments and there had to be knowledge of the reliability and limitations of the method in view of its subjective nature.Over about ten years, experience has been gained ~hich provi?es opportunities to optimize future experunentaJ des1gn and to appreciate when credibility has been over-